Caloric restriction has been shown to increase life span in organisms from yeast to mice and was recently reported to reduce age-related mortality and disease in the rhesus monkey. Drugs that mimic the effects of caloric restriction are actively being developed in the hopes that they will prove therapeutic toward a variety of age-related diseases in people. Despite the potential benefits of such caloric restriction mimetics, there are examples in each of the model organisms commonly used in aging-related research demonstrating that specific genotypic changes can block the longevity benefits of caloric restriction. Some genetic variants even have their life span shortened by caloric restriction. Little is known about the mechanisms underlying such genotype-dependent responses to caloric restriction, however, and there is currently no way of predicting how individuals in a genetically heterogenous population (such as humans) will respond to caloric restriction. Obtaining such an understanding is critically important before caloric restriction mimetics can be applied to improve human health. The goal of this proposal is first to address this question on a genome-wide scale in the budding yeast Saccharomyces cerevisiae, second to extend these findings to the nematode Caenorhabditis elegans, and third to begin identification and testing of human functional variants corresponding to factors identified fron the yeast and nematode studies. This will be accomplished by determining the replicative life span response of 1500 single- gene deletion mutants to caloric restriction, defining genetic variants that respond abnormally to caloric restriction, and characterizing the molecular mechanisms accounting for these effects. Nematode homologs of abnormally responding variants will be identified and experiments will be performed on a subset of these variants to determine which genotype-dependent responses to caloric restriction are conserved across these two widely divergent eukaryotes. Human homologs will also be identified and, in cases where they complement the yeast mutation, known sequence variants will be tested for functional significance in the response to caloric restriction. In this way, we will begin to gain insight into the interplay between genotype and the response to caloric restriction as well as the molecular mechanism that underlie this interplay.